Neuropeptide Y (NPY) has been implicated in a variety of pathological conditions including: cardiovascular and respiratory abnormalities, Parkinson's disease, depression and Alzheimer's disease. A program of rational drug design to develop non-peptide NPY analogs for intervention in these disorders would be facilitated by a structural model of the NPY binding site. The construction of such a model in turn requires an understanding of the molecular interactions between NPY peptide ligands and their receptors. In Phase I we will generate an interactive molecular model of the NPY receptor/ligand complex. The model will be tested by structurally modifying cloned NPY1 and NPY3 receptor subtypes using site-directed mutagenesis, and assessing the impact of these changes on the pharmacology of the receptors when expressed in heterologous cell lines. Results of these mutagenesis experiments will be used to further refine our model of NPY receptors and map their ligand binding sites. The models ability to simulate docking of proposed drug designs with their receptor targets will allow us, in Phase II, to expand our structure function studies of the NPY system and accelerate our design of lead compounds to rapidly develop therapeutically useful non-peptide analogs of NPY.